Identification of RIPK1 as a novel target for angiogenesis regulation based on ABT-869 conjugated photoaffinity...

Angiogenesis plays an important role in the stages of tumor initiation, development, metastasis and invasion. Angiogenesis regulation has gradually emerged as an effective strategy for clinical anti-tumor therapy and prognosis. The discovery and confirmation of new targets for angiogenesis regulation have establish a foundation for the development of novel and original drugs. Receptor-interacting protein kinase 1 (RIPK1), as a key regulator of necroptosis, has recently been found to have a novel function of altering vascular permeability. ABT-869, a multi-target inhibitor against the VEGFR and PDGFR families, has also been shown to be a novel inhibitor of RIPK1-mediated cell necrosis. Therefore, the exploration of whether RIPK1 can be used as the target of vascular permeability regulation and angiogenesis regulation by ABT-869 has high clinical application value. To this end, we adopted a photoaffinity labeling strategy to construct a multifunctional photoaffinity probe based on ABT-869, and verified the feasibility of the strategy with the known target VEGFR-2 as a model. Meanwhile, RIPK1 was identified as a potential angiogenic target of ABT-869 and its activity was further verified. The results of this study are expected to provide a new target for angiogenesis regulation and lay a foundation for the development of novel angiogenesis regulation drugs.